The invention relates to novel compounds which are used in the pharmaceutical industry as active compounds for preparing medicaments.
U.S. Pat. No. 4,468,400 describes tricyclic imidazo[1,2-a]pyridines having different ring systems fused to the imidazopyridine skeleton, which compounds are said to be suitable for treating peptic ulcer disorders. The international Patent Application WO95/27714 describes certain 8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridines having gastric acid secretion-inhibiting properties. The international Patent Applications WO98/42707 and WO98/54188 disclose tricyclic imidazopyridine derivatives having a very particular substitution pattern, which compounds are likewise said to be suitable for treating gastroin-testinal disorders.
The invention provides compounds of the formula 1
in which
R1 is methyl or hydroxymethyl,
one of the substituents R2a and R2b is hydrogen and the other is hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methoxyethoxy or methoxypropoxy,
one of the substituents R3a and R3b is hydrogen and the other is hydrogen, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methoxyethoxy or methoxypropoxy,
R4 is halogen, carboxyl, xe2x80x94CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical xe2x80x94COxe2x80x94NR5R6,
where
R5 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
R6 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R5 and R6 together with the nitrogen atom to which both are attached are a pyrrolidino, piperidino or morpholino radical,
X is O (oxygen) or NH,
and their salts,
except for those compounds in which R4 is chlorine or bromine if R2a or R2b is hydroxyl and simultaneously one of the substituents R3a and R3b is hydrogen and the other is hydrogen or hydroxyl.
For the purposes of the invention, halogen is bromine, chlorine or fluorine.
1-4C-Alkyl denotes straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
1-4C-Alkoxy denotes radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radicals.
Hydroxy-1-4C-alkyl denotes the abovementioned 1-4C-alkyl radicals substituted by a hydroxyl group. Examples which may be mentioned are the hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl radical.
1-4C-Alkoxy-1-4C-alkyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the methoxymethyl, the methoxyethyl and the butoxyethyl radical.
1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkyl denotes one of the abovementioned 1-4C-alkoxy-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxy radicals. An example which may be mentioned is the methoxyethoxymethyl radical.
Fluoro-1-4C-alkoxy-1-4C-alkyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by a fluoro-1-4C-alkoxy radical. Here, fluoro-1-4C-alkoxy denotes one of the 1-4C-alkoxy radicals which is fully or partly fluorine-substituted. Examples of fully or partly fluorine-substituted 1-4C-alkoxy which may be mentioned are the 1,1,1,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1,1,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy and the trifluoromethoxy and preferably the difluoromethoxy radical.
1-7C-Alkyl denotes straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
Suitable salts of compounds of the formula 1 are in particular all acid addition salts. Particular mention may be made of the pharmacologically acceptable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are employed in the salt preparation in an equimolar ratio or a ratio differing therefrom, depending on whether the acid is a mono- or polybasic acid and on which salt is desired.
Pharmacologically unacceptable salts, which can be initially obtained, for example, as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into the pharmacologically acceptable salts by processes known to the person skilled in the art.
It is known to the person skilled in the art that the compounds according to the invention and their salts can, for example when they are isolated in crystalline form, comprise varying amounts of solvents. The invention therefore also embraces all solvates and, in particular, all hydrates of the compounds of the formula 1, and all solvates and, in particular, all hydrates of the salts of the compounds of the formula 1.
The compounds of the formula 1 have at least two chiral centers. The invention provides all feasible stereoisomers in any mixing ratio, including the pure enantiomers which are the preferred subject matter of the invention.
One embodiment (embodiment a) of the invention are compounds of the formula 1, in which R4 is halogen.
A further embodiment (embodiment b) of the invention are compounds of the formula 1 in which R4 is carboxyl, xe2x80x94CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical xe2x80x94COxe2x80x94NR5R6.
Emphasis is given to compounds of the formula 1* 
in which
R1 is methyl or hydroxymethyl,
one of the substituents R2a and R2b is hydrogen and the other is hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methoxyethoxy or methoxypropoxy,
one of the substituents R3a and R3b is hydrogen and the other is hydrogen, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methoxyethoxy or methoxypropoxy,
R4 is halogen, carboxyl, xe2x80x94CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4 C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical xe2x80x94COxe2x80x94NR5R6,
where
R5 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
R6 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R5 and R6 together with the nitrogen atom to which both are attached are a pyrrolidino, piperidino or morpholino radical,
X is O (oxygen) or NH,
and its salts,
except for those compounds in which R4 is chlorine or bromine if R2a is hydrogen and R2b is hydroxyl and simultaneously R3a is hydrogen or hydroxyl and R3b is hydrogen.
Compounds of embodiment a of the invention which are to be emphasized are those of the formula 1* in which R4 is halogen.
Compounds of embodiment b of the invention which are to be emphasized are those of the formula 1* in which R4 is carboxyl, xe2x80x94CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical xe2x80x94COxe2x80x94NR5R6.
Particular emphasis is to be given to compounds of the formula 1*
in which
R1 is methyl,
one of the substituents R2a and R2b is hydrogen and the other is methoxy, ethoxy, propoxy, isopropoxy, butoxy, methoxyethoxy or methoxypropoxy,
one of the substituents R3a and R3b is hydrogen and the other is hydrogen or hydroxyl,
R4 is fluorine, chlorine, hydroxymethyl, methoxymethyl, methoxyethoxymethyl, difluoromethoxymethyl or the radical xe2x80x94COxe2x80x94NR5R6,
where
R5 is hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl or 2-methoxyethyl and
R6 is hydrogen, methyl or ethyl,
X is O (oxygen) or NH,
and their salts.
Compounds of embodiment a of the invention which are to be particularly emphasized are those of the formula 1* in which R4 is fluorine or chlorine.
Compounds of embodiment b of the invention which are to be particularly emphasized are those of the formula 1* in which R4 is hydroxymethyl, methoxymethyl, methoxyethoxymethyl, difluoromethoxymethyl or the radical xe2x80x94COxe2x80x94NR5R6, or 2-methoxyethyl and R6 is hydrogen, methyl or ethyl.
Among all the compounds of formula 1*, preference is given to those in which R3a is hydroxyl. In the Examples below, the absolute configuration xe2x80x9cRxe2x80x9d for both positions 8 and 9 has been assigned to these compounds of formula 1* in which R3a is hydroxyl.
The following exemplary preferred compounds according to the invention may be mentioned specifically using the general formula 1* and the meanings of the substituents R1, R2a, R2b, R3a, R3b, R4 and X of Table 1 (Tab. 1) below:
and the salts of these compounds.
The compounds according to the invention can be prepared as described in the examples below in an exemplary manner, or by employing similar process steps using appropriate starting materials (see, for example, WO 98/42707, WO 98/54188, EP-A-299470 or Kaminski et al., J. Med. Chem. 1985, 28, 876-892 and Angew. Chem. 1996, 108, 589-591). The starting materials are known, or they can be prepared in a manner similar to that for known compounds. The compounds according to the invention can be prepared, for example, in accordance with the reaction schemes below. 
In scheme 1 above, the enantioselective synthesis of a 7,8-diol according to the invention (R2a or R2b and R3a or R3b are in each case hydroxyl) is shown in an exemplary manner; if desired, the diol can subsequently be etherified in a suitable manner.
Group Y in compound 3 above is a suitable leaving group, for example a halogen atom, preferably chlorine. The acylation is carried out in a manner familiar to the person skilled in the art, preferably using sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide, if the leaving group is a chlorine atom.
The oxidation that follows after the acylation is likewise carried out under customary conditions using the oxidizing agent chloranil, atmospheric oxygen or manganese dioxide. For the subsequent removal of protective groups and cyclization, certain conditions have to be met with respect to the auxiliary acid used. Advantageously, the auxiliary acid used according to the invention is formic acid.
The reduction to the diol is likewise carried out under standard conditions (see, for example, WO 98/54188), where the reducing agent used is, for example, sodium borohydride, the use of which allows the given 7,8-trans-diol to be obtained in a diastereomeric purity of more than 90%. Etherification, which is carried out subsequently, if desired, and which is likewise carried out in a usual manner, gives the compounds of the formula 1* according to the invention in which R2a and R3b are hydrogen.
To prepare compounds of the formula 1 in which R3a and R3b are hydrogen, 3-hydroxy-3-phenylpropionic acid derivatives (which are appropriately protected at the hydroxyl group), in which Y (analogously to the scheme above) is a suitable leaving group, have to be used as starting materials in place of compound 3. 
Scheme 2 above also represents, in an exemplary manner, an enantioselective synthesis. Y again denotes a suitable leaving group, for example a methoxy group. Depending on whether a compound where R3a and R3b=hydrogen or a compound where R3a or R3b=hydroxyl is desired, the group G denotes either hydrogen or a hydroxyl group (which is, for example, protected by a suitable silyl radical).
Reduction of the keto group with sodium borohydride, which follows after the cyclization, givesxe2x80x94if G is a hydroxyl groupxe2x80x94the 7,8-trans-diol in a diastereomeric purity of more than 90%. Subsequent etherification, which is carried out by known processes, gives the end products of the formula 1* in which R2a and R3b are hydrogen. The corresponding 7,8-cis compound is obtained by chromatographic purification from the mother liquor which remains after the 7,8-trans compound has been separated off.
The substances according to the invention are isolated and purified in a manner known per se, for example by distilling off the solvent under reduced pressure and recrystallizing the resulting residue from a suitable solvent, or by subjecting it to one of the customary purification methods, such as, for example, column chromatography on a suitable stationary phase.
Salts are obtained by dissolving the free compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or in a low-molecular-weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or to which the desired acid is subsequently added. The salts are obtained by filtration, reprecipitation, precipitation with a nonsolvent for the addition salt or by evaporating the solvent. The resulting salts can be converted by alkalization or acidification into the free compounds which in turn can be used to prepare salts. In this manner, it is possible to convert pharmacologically unacceptable salts into pharmacologically acceptable salts.
The pure enantiomers, in particular the pure enantiomers of the formula 1*, which are preferably provided by the invention, can be obtained in a manner familiar to the person skilled in the art, for example by enantioselective synthesis (see, for example, the scheme), by chromatographic separation on chiral separation columns, by derivatization with chiral auxiliaries, subsequent separation of the diastereomers and removal of the chiral auxiliary group, by salt formation with chiral acids, subsequent separation of the salts and liberation of the desired compound from the salt, or by (fractional) crystallization from a suitable solvent.
The resulting etherified trans products (for example compounds 1* where R2a and R3b=hydrogen) canxe2x80x94at least partiallyxe2x80x94be converted into the corresponding cis products (for example where R2b and R3b=hydrogen) by allowing the product to stand under acidic conditions (for example in 2 equivalents of acid, such as sulfuric acid) in the corresponding alcohol R2axe2x80x94OH. Likewise, cis products can be converted into the corresponding trans products. The cis and trans products are separated, for example, by chromatography or by crystallization.
The starting materials of the formula 2 can be prepared from compounds known from the literature or by working analogously to processes known from the literature (for example Kaminski et al., J. Med. Chem. 1985, 28, 876-892), for example according to the general scheme 3 below: 
The conversion into compound 4 is carried out in a manner known to the person skilled in the art. Conversion of 4 into 5 can be carried out by different routes, for example using the Heck reaction (with Pd(II), carbon monoxide and ethanol) or by metallation in the 6-position (with lithium or magnesium) and subsequent Grignard reaction. By metallation, it is also possible to introduce other desired groups R4 into position 6, for example fluorine, chlorine or the carboxyl group. Starting with the ester group, it is possible to introduce further desired groups R4 into position 6, for example hydroxy-1-4C-alkyl radicals (in particular the hydroxymethyl radical) by reducing the ester radical with lithium aluminum hydride, or 1-4C-alkoxy-1-4C-alkyl radicals (in particular 1-4C-alkoxymethyl radicals) by subsequent etherification as outlined in Scheme 3.
Debenzylation/reduction of the compounds 5 and 6 is likewise carried out in a manner known per se, for example by using hydrogen/Pd(O). If the desired compounds are compounds where R4=xe2x80x94COxe2x80x94NR5R6, a corresponding derivatization can be carried out in a manner known per se (conversion of an ester into an amide) at the stage of compound 5 or after debenzylation/reduction, or alternatively at the stage of the acyloin (see Schemes 1 and 2).
The following examples illustrate the invention in more detail, without limiting it. Further compounds of the formula 1 whose preparation is not described explicitly can likewise be prepared in an analogous manner or in a manner known per se to the person skilled in the art, using customary process techniques. The abbreviation min stands for minute(s), h stands for hour(s) and ee stands for enantiomeric excess. In some successive examples the preparation of pairs of diastereoisomers is described. In case of the pairs 7R,8R,9R/7S,8R,9R, the diastereoisomers can be separated by column chromatography with the 7S,8R,9R diastereolsomer being contained in the first and the 7R,8R,9R diastereoisomer being contained in the second main fraction.